Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer. The disorder is characterized by breakdown of the oral mucosa, which results in the formation of ulcerative lesions. In granulocytopenic patients, the ulcerations that accompany mucositis are frequent portals of entry for indigenous oral bacteria often leading to sepsis or bacteremia. Mucositis occurs to some degree in more than one third of all patients receiving anti-neoplastic drug therapy. The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant. Among these individuals, moderate to severe mucositis (ulceration) is not unusual in more than three-quarters of patients. Moderate to severe mucositis occurs in virtually all patients who receive radiation therapy for tumors of the head and neck and typically begins with cumulative exposures of 15 Gy and then worsens as total doses of 60 Gy or more are reached.
Clinically mucositis progresses through four stages: (1) An initial stage that is characterized by inflammatory changes of erythema and edema. Localized islands of hyperkeratosis may also been seen. This stage is symptomatically mild and may be successfully palliated by topical anesthetics. (2) Subsequently the mucosa breaks down and becomes eroded and atrophic with increasingly significant inflammatory changes. This stage is increasingly painful and may require systemic analgesic therapy in the form of NSAIDs or oral narcotics for adequate palliation. (3) The third stage of mucositis is the most symptomatic. Full thickness ulcers of the mucosa cause severe discomfort necessitating parenteral narcotic therapy. In addition, in the myelosuppressive patient, these ulcerations provide a systemic portal of entry for the oral microflora often leading to bacteremia and sepsis. Antimicrobial intervention is required. (4) Finally, spontaneous healing occurs about 2-3 weeks after cessation of anti-neoplastic therapy.
The complexity of mucositis as a biological process has only been recently appreciated. The condition appears to represent a sequential interaction of oral mucosal cells and tissues including connective tissue, endothelium, epithelium and inflammatory cells, pro-inflammatory cytokines and local environmental factors such as bacteria and saliva. Damage to epithelial and connective tissue induces release of inflammatory cytokines leading to mucosal damage. Additionally, both direct and indirect effects to epithelial cells result in either apoptotic or necrotic changes in the basal layer; differentiation into new epithelial cells is halted. The arrest of epithelial cell renewal leads to atrophy followed by ulceration.
Standard therapy for mucositis is predominantly palliative, including application of topical analgesics such as lidocaine and/or systemic administration of narcotics and antibiotics. Thus, there is a need for new treatments which inhibit, prevent, reduce the severity, and/or promote the healing of mucositis.
The invention relates to the unexpected discovery that bismuth-containing compounds are effective in the treatment of oral mucositis in a mammal (see Example 7). Thus, the invention relates, in one aspect, to a method of treating oral mucositis comprising administering an effective amount of a pharmaceutically acceptable bismuth-containing compound, such as a bismuth salt or bismuth complex. In one preferred embodiment, the bismuth compound is an organic or inorganic salt such as, bismuth subsalicylate, bismuth subgallate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth carbonate, bismuth subcarbonate, tripotassium dicitrato bismuthate, bismuth nitrate, bismuth subnitrate, bismuth tartrate and mixtures thereof, preferably, bismuth subsalicylate and bismuth subgallate. Other examples include bismuth acetyl histidine, bismuth benzoate, bismuth salicylate basic, bismuth formate, bismuth acetate, bismuth propionate, bismuth butyrate and bismuth salicylate. In another preferred embodiment, the bismuth compound is the salt of an amino acid or a peptide, preferably an antimicrobial peptide (e.g., maganin, cecoropin and iseganin).
Another embodiment of the present invention is the described bismuth salts for use in the manufacture of a medicament for the treatment or prevention of oral mucositis.
As stated above, the invention relates to the unexpected discovery that bismuth-containing compounds are effective in the treatment of oral mucositis in a mammal. Oral mucositis is defined herein as inflammation of a mucous membrane of the oral cavity or lips. Thus, the invention relates, in one aspect to a method of treating oral mucositis comprising administering an effective amount of a pharmaceutically acceptable bismuth-containing compound, such as a bismuth salt or bismuth complex. In one preferred embodiment, the bismuth compound is an organic or inorganic salt such as, bismuth subsalicylate, bismuth subgallate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth carbonate, bismuth subcarbonate, tripotassium dicitrato bismuthate, bismuth nitrate, bismuth subnitrate, bismuth tartrate and mixtures thereof, preferably, bismuth subsalicylate and bismuth subgallate. Other examples include bismuth acetyl histidine, bismuth benzoate, bismuth salicylate basic, bismuth formate, bismuth acetate, bismuth propionate, bismuth butyrate and bismuth salicylate. In another preferred embodiment, the bismuth compound is the salt of an amino acid or a peptide, preferably an antimicrobial (e.g., maganin, cecoropin and iseganin). Additionally, the invention includes the use of the described bismuth-containing compounds for use in the manufacture of a medicament for the treatment or prevention of oral mucositis.
Bismuth-containing compounds and pharmaceutical compositions thereof suitable for use in the present invention are generally known in the art. Various bismuth salts and complexes have been described for use in the treatment of various gastrointestinal disorders, including peptic ulcers of the esophagus, stomach or duodenum and for preventing gastrointestinal distress. These formulations include Pepto-Bismol(copyright) (the Proctor and Gamble Company, bismuth subsalicylate in a methylcellulose/magnesium aluminum silica suspension). See, also, U.S. Pat. Nos. 5,013,560, 4,801,454 and 4,940,695, the contents of which are incorporated herein by reference.
When the bismuth-containing compound is a salt, bismuth is preferably in the +3 oxidation state but can also be in the +5 oxidation state. The counteranions in the bismuth salt can all be the same, or, in the alternative, can be different. Bismuth salts which contain two or more different counteranions are said to be xe2x80x9cmixedxe2x80x9d. Alternatively, the bismuth-containing compound can be bismuth metal, i.e., bismuth in the zero oxidation state.
In another preferred embodiment, the bismuth salt is the salt of a non-steroidal anti-inflammatory agent (hereinafter xe2x80x9cNSAIDxe2x80x9d). Preferred NSAIDs have at least one acidic functional group, such as a carboxylic acid, sulfonic acid, phosphoric acid, sulfinic acid, phenol or thiol functional group, so that the compound can readily form an anion and bond ionically with bismuth. Specific examples of suitable NSAIDs include aminoarylcarboxylic acid derivatives (e.g., Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid), arylacetic acid derivatives (e.g., Acematicin, Alclofenac, Amfenac, Bufexamac, Caprofen, Cinmetacin, Clopirac, Diclofenac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid, Fenoprofen, Fentiazac, Flubiprofen, Glucametacin, Ibufenac, Ibuprofen, Indomethacin, Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Metiazinic Acid, Naproxen, Oxametacine, Proglumrtacin, Sulindac, Tenidap, Tiramide, Tolectin, Tolmetin, Zomax and Zomepirac), arylbutyric acid ferivatives (e.g., Bumadizon, Butibufen, Fenbufen and Xenbucin) arylcarboxylic acids (e.g., Clidanac, Ketorolac and Tinoridine), arylproprionic acid derivatives (e.g., Alminoprofen, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Piketoprofen, Piroprofen, Pranoprofen, Protinizinic Acid, Suprofen and Tiaprofenic Acid), pyrazoles (e.g., Difenamizole and Epirizole), pyrazolones (e.g., Apazone, Benzpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphenbutazone, Phenylbutazone, Pipebuzone, Propyphenazone, Ramifenazone, Suxibuzone and Thiazolinobutazone), salicyclic acid derivatives (e.g., Acetaminosalol, 5-Aminosalicylic Acid, Aspirin, Benorylate, Biphenyl Aspirin, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Flufenisal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine Salicylate, 1-Naphthyl Sallicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, 2-Phosphonoxybenzoic Acid, Salacetamide, Salicylamide O-Acetic Acid, Salicylic Acid, Salicyloyl Salicylic Acid, Salicylsulfuric Acid, Salsalate and Sulfasalazine), thiazinecarboxamides (e.g., Droxicam, Isoxicam, Piroxicam and Tenoxicam), xcex5-Acetamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine, Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Ketorolac, Meclofenamic Acid, Mefenamic Acid, Nabumetone, Nimesulide, Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime, Piroxicam, Proquazone and Tenidap.
In another preferred embodiment, the bismuth salt is the salt of an antimicrobial agent. Preferred antimicrobial agents are those which have at least one acidic functional group, so that the compound can readily form an anion and bond ionically with bismuth. Specific examples of suitable antimicrobial agents include pencillins (e.g., Benzyl penicillin, P-hydroxybenzyl penicillin, 2-pentenyl penicillin, N-heptyl penicillin, phenoxymethyl penicillin, Phenethicillin, Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillino, Nafcillin, Ampicillin, Amoxicillin, Cyclacillin, Carbenicillin, Ticarcillin, Piperacillin, Azlocillin, Meczlocillin, Mecillinam, Amdinocillin), Cephalosporin and derivatives thereof (e.g, Cephalothin, Cephapirin, Cephacetrile, Cephazolin, Caphalexin, Cephandine, Cefadroxil, Cefamandol, Cefuroxime, Ceforanide, Cefoxitin, Cefotetan, Cefaclor, Cefotaxime, Ceftizoxime, Ceftrioxone, Ceftazidime, Moxalactam, Cefoperazone, Cefixime, Ceftibuten and Cefprozil), Oxolinic Acid, Amifloxacin, Temafloxacin, Nalidixic Acid, Piromidic Acid, Ciprofloxacin, Cinoxacin, Norfloxacin, Perfloxacin, Rosaxacin, Ofloxacin, Enoxacin, Pipemidic Acid, Sulbactam, Clavulinic Acid, xcex2-Bromopenicillanic Acid, xcex2-Chloropenicillanic Acid, 6-Acetylmethylene-Penicillanic Acid, Cephoxazole, Sultampicillin, Formaldehyde Hudrate Ester of Adinocillin and Sulbactam, Tazobactam, Aztreonam, Sulfazethin, Isosulfazethin, Norcardicins, m-Carboxyphenyl Phenylacetamidomethylphosphonate, Chlortetracycline, Oxytetracyline, Tetracycline, Demeclocycline, Doxycycline, Methacycline and Minocycline.
In another preferred embodiment, the bismuth salt is mixed and is the salt of an antimicrobial agent and an NSAID.
In another preferred embodiment, the bismuth salt is one of the salts described above, provided however, that the salt does not comprise an antioxidant or free radical scavenger.
In another preferred embodiment, the bismuth salt is mixed and is the salt of an antimicrobial agent and an antioxidant or free radical scavenger. Suitable antioxidants and free radical scavengers generally have at least one acidic functional group, so that the antioxidant or free radical scavenger can readily form an anion and bond ionically with bismuth. In a preferred embodiment, the antioxidant or free radical additionally comprise a phenol, a phoshorothioate, a thiol or one or more double bonds which readily oxidize or readily react with free radicals. Examples of suitable phenol-containing compounds include 2,6-di-tert-butyl-4-methoxy phenol, 2,6-di-tert-butyl-4-methyl phenol, xcex1-tocopherol, retinoic acid and catechol; examples of suitable thiol-containing compounds include N-acetylcysteine, mercaptoethylamine and glutathione; examples of suitable phosphorothioates include amifostine; and examples of suitable double bond-containing compounds include ascorbic acid and dehydroascorbic acid.
In yet another preferred embodiment, the bismuth salt is mixed and is the salt of an NSAID and an antioxidant or free radical scavenger.
The bismuth-containing compound is generally locally administered to the lesion in the mouth. This can be accomplished by administering an aqueous suspension of the compound or by administering a powder or tablet which is then masticated. The composition can be applied directly to the lesion, e.g., by a swab, or by other means, such as in a mouthwash or rinse. Preferably, the compound is administered as a suspension, either by a swab or by a rinse.
An xe2x80x9ceffective amountxe2x80x9d of the compound or composition is the quantity which results in a desired therapeutic or prophylactic effect with respect to oral mucositis. xe2x80x9cA desired therapeutic effectxe2x80x9d includes an amelioration of the discomfort associated with the oral mucositis and/or an increase in the rate of healing of lesions associated with oral mucositis. A xe2x80x9cdesired prophylactic effectxe2x80x9d includes a reduced number of lesions and/or reduced size of mucositis lesions compared with, for example, what is normally experienced by a mammal undergoing cancer therapy. Typically, an xe2x80x9ceffective amountxe2x80x9d is between about 0.1 mg/day to about 10 grams/day applied to or contacted with the lesion(s) or oral mucosal surface, and preferably between about 1.0 mg/day to about 1 gram/day and more preferably between about 10 mg/day to about 500 mg/day.
The composition can be administered to the patient as needed to provide amelioration or prevention (inhibition) of the symptoms. For example, the composition can be administered one, two, three, four or more times daily. In another embodiment, the composition is administered following meals and/or other fluid intake and/or as the saliva dissolves or removes the composition from the lesions.
Preferred suspensions of the bismuth-containing compound include aqueous suspensions further comprising an anionic or a non-ionic cellulose ether. Examples of nonionic cellulose ethers include alkyl-celluloses (e.g., methylcellulose), hydroxyalkylalkylcelluloses (e.g., hydrocyclopropylmethylcellulose; hydroxybutylmethylcellulose; hydroxyethylmethylcellulose; ethylhydroxyethylcellulose), hydroxyalkylcelluloses (e.g., hydroxyethylcellulose; hydroxypropylcellulose), and mixtures thereof. Most preferred are alkylcelluloses, especially methylcellulose. Pharmaceutically-acceptable non-ionic cellulose ether polymers are well known in the art, and are described in more detail in xe2x80x9cHandbook of Water-Soluble Gums and Resinsxe2x80x9d (McGraw-Hill Book Company, New York; 1980; Davidson, editor), chapters 3, 12, and 13, the disclosures of which are incorporated herein by reference in their entirety. An anionic cellulose ether includes carboxymethyl cellulose.
Representative examples of pharmaceutically-acceptable non-ionic cellulose ether polymers useful in the compositions of the present invention are: Methocel A(copyright) (methylcellulose, sold by the Dow Chemical Company); Metolose SM(copyright) (methylcellulose, sold by Shin Etsu Chemical Products Ltd.); and Methocel E(copyright) (hydroxypropylmethylcellulose, sold by the Dow Chemical Company).
The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.1% to about 25% or more of a non-ionic cellulose ether polymer, preferably from about 0.1% to about 10%, more preferably from about 0.5% to about 3%, and most preferably from about 0.5% to about 1.5%.
Alternatively or additionally, the composition can contain other high molecular weight polysaccharides, such as a xanthan or guar gum. Xanthan gum is available from a variety of commercial sources, including Rhodigel(copyright) (sold by Rhone Poulenc Industries) and Keltrol(copyright) (sold by Kelco Division of Merck and Co., Inc.). Xanthan gum is typically used at a level of from about 0.1% to about 5%, preferably from about 0.1% to about 3%, and more preferably from about 0.5% to about 1.5%.
The suspension further preferably comprises a magnesium aluminum silcate. Magnesiuim aluminum silicate (or aluminum magnesium silicate) is of the formula Al2MgO8Si2, occurring naturally in such smectite minerals as colerainite, saponite, and sapphirine. Refined magnesium aluminum silicates useful herein are readily available, such as Veegum(copyright), magnesium aluminum silicate, manufactured by R. T. Vanderbilt Company, Inc.
The pharmaceutical compositions of the present invention typically comprise, by weight, from about 0.1% to about 25% or more of a magnesium aluminum silicate, preferably from about 0.1% to about 10%, more preferably from about 0.1% to about 5%, and most preferably from about 0.1% to about 5%, and most preferably from about 0.5% to about 1.5%.
In addition to the essential components described hereinbefore, the pharmaceutical compositions of the present invention may comprise additional optional components selected as appropriate for the particular orally-administrable dosage form being used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders, as well as the preferred aqueous liquid forms. Tablets can be compressed, tablet triturates, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
Liquid oral dosage forms are preferred herein. Compositions herein in the form of a liquid include, for example, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. They may contain suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents, and/or flavoring agents. Preferably, these liquid dosage forms comprise water, typically at a level by weight of from about 75% to about 99%, preferably from about 85% to about 98%, and most preferably from about 92% to about 96%.
Some examples of substances which can serve as pharmaceutically-acceptable optional components are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; and polyols such as propylene glycol, glycerine, sorbitol, mannitol, polyethylene glycol, benzoic acid, methylsalicylate, salicylic acid, and salts thereof, sodium saccharin, sorbic acid, aspartame, acesulfome and cyclamate. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, anti-oxidants (preferably antioxidants which do not have acidic functional groups) and preservatives can also be present.
The choice of pharmaceutically-acceptable optional components to be used in the compositions of the present invention is basically determined by the form and aesthetic properties desired for the composition. Pharmaceutically-acceptable optional components suitable for the preparation of compositions herein for oral administration are well known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.
In one preferred embodiment, the suspension employed herein is Pepto-Bismol(copyright) (containing 1.75% bismuth subsalicylate, about 1% methylcellulose and about 1% Veegum(copyright)) or an equivalent suspension omitting the flavorant and/or colorant. Other bismuth-containing composition include De-Nol(copyright) (bismuth subcitrate; Gist-Brocades, N.V.), Noralac(copyright) (bismuth aluminate, alginic acid and magnesium carbonate; North American Pharmaceuticals), Roter(copyright) bismuth (bismuth subnitrate; Roter Laboratories), and Fensobar Polvo(copyright) (bismuth subcarbonate, USV Pharmaceutical Corp.).
In yet another embodiment, the composition further comprises an antimicrobial agent (e.g., antibacterial, antiviral and antifungal agents), such as chlorhexidine, triclosan, iodine complexes, tetracyclines, metronidazole, bacitracin, neomycin, polymyxin B, tobramycin, vidariabine, denavir, acyclovir, gancyclovir, foscarnet, famcyclovir, nystatin, emphotericin, flucytocine, itraconazole, fluconazole, clotrimazole, and econazole, to prevent or treat infections of the lesions. The antimicrobial agent can also be a polymer, such as the antimicrobial polymers disclosed in Mandeville, III et al., xe2x80x9cIonic Polymers as Anti-Infective Agentsxe2x80x9d, U.S. Pat. No. 6,034,129, and Kurtz and Neenan; xe2x80x9cAntimicrobial Compositions and Methodsxe2x80x9d, U.S. Ser. No. 09/568,825, filed May 11, 2000 which is now U.S. Pat. No. 6,482,402; and Kurtz and Fitzpatrick, xe2x80x9cAnionic Polymers as Toxin Bindersxe2x80x9d, U.S. Ser. No. 09/541,268, filed Apr. 3, 2000 which is now U.S. Pat. No. 6,270,755.
Alternatively or additionally, the composition can further comprise an anti-inflammatory agent, such as aspirin, acetaminophen or ibuprofen, salicylic acid, salicyloyl salicylic acid (disalcid), salicylamide, diflunisal (dolobid), mefenamic acid (ponstel), mellofenamic acid (meclomen), fenoprofen (nalfon), ketoprofen (orodis), flubiprofen (ansaid), naproxen (naprosyn), diclofenas (voltaren), benorylate (benoral), caprofen (rimadyl), sulindac (clinoril), piroxicam, oxyphenylbutazone (tanderil), phenylbutazone (butazolidin), metiazinic acid, zomepirac, zomax, ketorolac (toradol), etodolac (Iodine), tolmetin, tolectin, indomethacin (indocin), tenidap (enablex) and/or an anesthetic agent, such as benzydamine, dyclonine, diphenylhydramine, benzocaine, cocaine and lidocaine.
The method of the claimed invention is particularly useful in the treatment of oral mucositis resulting from anti-cancer therapy, such as radiation therapy or chemotherapy, including induction therapy in leukemia patients. xe2x80x9cTreatmentxe2x80x9d includes both prophylactic and/or therapeutic treatment. The treatment can be particularly beneficial for patients undergoing treatment for tumors of the head and neck, such as radiation patients. For prophylactic treatment of mucositis resulting from chemotherapy, treatment with the bismuth salt is initiated before the onset of the chemotherapy, during chemotherapy, after chemotherapy is completed but before symptoms appear or any combination of the above. For prophylactic treatment of mucositis resulting from radiation therapy, treatment with the bismuth salt is initiated before the onset of radiation therapy, during radiation exposure, after radiation exposure has been terminated (preferably no sooner than about one hour, more preferably five hours after termination) but before symptoms appear or any combination of the above. Prophylactic treatment includes inhibiting the onset of mucositis, delaying the onset of mucositis, reducing the severity of mucositis and/or reducing the likelihood of developing mucositis. For therapeutic treatment of mucositis resulting from radiation therapy or chemotherapy, the bismuth salt is administered after symptoms of mucusitis (e.g., mouth ulcers) have appeared.
The method is preferably used with human patients, but can also be used with other mammals, such as companion animals (e.g., dogs, cats, and the like), farm animals (horses, cattle and the like) and laboratory animals (hamsters, mice, rats and the like).